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Yasuo Yamaguchi,
Fujio Matsumura, Jian Liang,
Eiji Akizuki,
Teishi Matsuda,
Kazutoshi Okabe,
Hajime Ohshiro,
Kohjiro Ishihara,
Shinwa Yamada,
Katsutaka Mori,
Michio Ogawa
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ABSTRACT: Interferon- is a key immunoregulatory cytokine involved in acute graft rejection. Immunologic unresponsiveness to organ allografts has been induced by pretransplantation donor-specific blood transfusion, both experimentally and clinically. We investigated interferon- production and intragraft gene expression of type-1 T-helper cytokines such as interleukin-12 and -18 and type-2 T-helper cytokines such as interleukin-10 and transforming growth factor- in rats receiving hepatic allografts after such transfusions. The animals were divided into four groups: group I received isografts; group II received allografts; group III received allografts after donor-specific transfusion; and group IV received allografts and was treated with FK 506. Donor blood given seven days prior to transplantation significantly prolonged allograft survival. The serum interferon- concentrations in group II increased, peaking on day 5 and then decreasing. Serum interferon- concentrations in groups I, III, and IV were significantly lower than those observed in group II, as were levels of interleukin-12 and interleukin-18 mRNA in the graft. Transforming growth factor- and interleukin-10 mRNA levels in grafts in transfused animals were significantly greater than those in the untreated allograft group. Interleukin-12 and -18 mRNA transcripts in an allogeneic mixed lymphocyte reaction were inhibited by interleukin-10 and transforming growth factor-. These results suggest that interleukin-12 and -18 expression in hepatic allografts is inhibited in the immunologically unresponsive state induced by donor-specific transfusion.
Digestive Diseases and Sciences 11/2000; 45(12):2429-2435. · 2.12 Impact Factor
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Jian Liang,
Yasuo Yamaguchi,
Fujio Matsumura,
Mataro Goto,
Eiji Akizuki,
Teishi Matsuda,
Kazutoshi Okabe,
Hajime Ohshiro,
Kohjiroh Ishihara,
Shinwa Yamada,
Katsutaka Mori,
Michio Ogawa
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ABSTRACT: We investigated the effects of the calcium-channel blocker verapamil hydrochloride on the production of cytokine-induced neutrophil chemoattractant (CINC) following reperfusion injury in rat liver. Ischemia was induced for 30 min by portal vein occlusion. Animals were pretreated with intravenous injection of verapamil hydrochloride (2.5 mg/kg) 5 min before vascular clamp. Verapamil hydrochloride limited increases in the chemoattractant compared with nonpretreated rats. Most cells immunostained for chemoattractant were ED2-positive macrophages in sinusoids. In vitro chemoattractant production by Kupffer cells isolated from animals pretreated with verapamil hydrochloride was significantly lower than by Kupffer cells from nonpretreated animals. Expression of transcripts in liver for chemoattractant peaked 3 hr after reperfusion in nonpretreated animals, while pretreatment with verapamil hydrochloride significantly decreased chemoattractant mRNA levels. In vitro chemoattractant production could be induced in naive Kupffer cells after stimulation with oxygen radicals generated by hypoxanthine and xanthine oxidase, but verapamil hydrochloride prevented these increases. We concluded that the calcium-channel blocker verapamil hydrochloride significantly attenuates chemoattractant release by Kupffer cells after ischemia–reperfusion in the rat liver.
Digestive Diseases and Sciences 12/1999; 45(1):201-209. · 2.12 Impact Factor
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ABSTRACT: Background. The monocyte chemoattractant protein-1 (MCP-1) is produced during reperfusion injury and induces tissue factor that is the initiator of the clotting cascade. Neutrophil elastase is a crutial mediator of inflammatory tissue damage. Activation of the coagulation system stimulates cytokine production by activated leukocytes. We investigated the effects of neutrophil elastase and oxygen radicals generated by hypoxia associated with microthrombus formation on MCP-1 expression after ischemia/reperfusion in rat liver.
Methods. In vitro MCP-1 production by macrophages after stimulation with human neutrophil elastase (HNE) or oxygen radicals generated by hypoxanthine and xanthine oxidase was examined. Liver ischemia was induced in rats by occluding the portal vein for 30 min. An inhibitor of human neutrophil elastase (ONO-5046·Na, 10 mg/kg) and antithrombin III (AT-III, 250 U/kg) were injected i.v. 5 min before vascular clamping. Serum concentrations of MCP-1 were measured by enzyme-linked immunosorbent assay.
Results. Human neutrophil elastase or oxygen radicals significantly enhanced in vitro MCP-1 production by macrophages. Serum MCP-1 concentrations reached a peak at 6 hr after reperfusion and then gradually decreased. However, pretreatment of animals with AT-III or ONO-5046·Na alone resulted in significantly smaller increases in serum concentrations of MCP-1 after reperfusion. Pretreatment with both ONO-5046·Na and AT-III produced additive effects. The combined treatment with ONO-5046·Na and AT-III significantly reduced MCP-1 mRNA in liver after ischemia/reperfusion.
Conclusions. MCP-1 production by macrophages is stimulated by neutrophil elastase and oxygen radicals generated by hypoxia, probably due to microthrombus formation after ischemia/reperfusion of the rat liver.
Transplantation 11/1999; 68(10):1459-1468. · 4.00 Impact Factor
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ABSTRACT: The role of nitric oxide (NO) on tissue injury of hepatic allografts during rejection remains controversial. We investigated inducible nitric oxide synthase (iNOS) expression and formation of peroxynitrite in ACI rat liver grafts implanted in recipients. Animals were divided into four experimental groups: group I, isografts; group II, untreated hepatic allografts; group III, allografts treated with FK506; and group IV, allografts pretreated with donor-specific blood transfusion (DST). Serum nitrite/nitrate, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) concentrations increased significantly in group II rats after transplantation but were significantly lower in groups I, III, and IV. The numbers of macrophages that reacted with an antimacrophage iNOS monoclonal antibody as well as iNOS messenger RNA (mRNA) levels in liver specimens were also much lower in groups I, III, and IV as compared with group II. Immunostaining and Western blot analysis showed prominent tissue nitrotyrosine expression in untreated hepatic allografts, but not in allografts treated with FK506 or donor-specific blood. These results suggest that one of the mechanisms by which production of NO results in injury in rat hepatic allografts may be because of its reaction with superoxide to form peroxynitrite.
Hepatology 02/1999; 29(3):777 - 784. · 11.66 Impact Factor
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Yasuo Yamaguchi,
Nobutomo Miyanari,
Osamu Ichiguchi,
Eiji Akizuki,
Fujio Matsumura,
Teishi Matsuda,
Kazutoshi Okabe, Jian Liang,
Hajime Ohshiro,
Katsutaka Mori,
Michio Ogawa M.D
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ABSTRACT: It has previously been shown that a single intravenous injection of freshly heparinized donor-specific blood transfusion (DST) before transplantation significantly prolongs the survival of fully allogeneic ACI (RT1a)-to-LEW(RT11) rat hepatic allografts. Additionally, we have shown that pretreatment of LEW rats with PVG.r1 blood, which shares only the RT1.A major histocompatibility complex (MHC) region with ACI, significantly prolongs the survival of ACI hepatic allografts. In this study, we report the cellular identity of hepatic allograft leukocyte infiltrates following transplantation. Fluorescence-activated cell sorting (FACS) analysis revealed that CD4+ T cells infiltrating liver allografts could be divided into two subsets, CD45RC−CD4+ and CD45RC+CD4+ T cells, and that the ratio of CD45RC−CD4+/CD45RC+ CD4+ T cells was significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood as compared to untreated allografts. Further, CD8+ T cells that accumulated in the liver grafts could be similarly divided into two subsets, and the ratio of CD45RC−CD8+/CD45RC+ CD8+ T cells was also significantly higher in hepatic allografts of recipients pretreated with DST or PVG.r1 blood. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis revealed that CD45RC−CD4+ T cells harvested from hepatic allografts pretreated with PVG.r1 blood expressed interleukin-4 (IL-4) and interleukin-10 (IL-10), but not interleukin-2 (IL-2) or interferon-γ (IFN-γ). In contrast, CD45RC−CD8+ T cells from hepatic allografts pretreated with PVG.r1 blood expressed IL-4, IL-10, and IFN-λ, but not IL-2. These results indicate that the CD45RC leukocyte common antigen could be used to differentiate CD4+ and CD8+ T cells following pretreatment with DST or PVG.r1 blood. Persistent infiltration of CD45RC−CD4+ and CD45RC−CD8+ T cells, capable of secreting Th2-type cytokines may prevent allograft rejection by causing immunologic unresponsiveness.
Hepatology 07/1998; 28(2):450 - 458. · 11.66 Impact Factor
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Teishi Matsuda,
Yasuo Yamaguchi,
Fujio Matsumura,
Eiji Akizuki,
Kazutoshi Okabe, Jian Liang,
Hajime Ohshiro,
Osamu Ichiguchi,
Shinwa Yamada,
Katsutaka Mori,
Michio Ogawa
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ABSTRACT: Background: Neutrophils may play an important role in the development of liver ischemia/reperfusion injury. We investigated the effects of the immunosuppressants azathioprine (AZA), cyclosporine A (CsA), tacrolimus (FK506), and rapamycin (RPM) on the expression of cytokine-induced neutrophil chemoattractant (CINC) after ischemia/reperfusion of the liver.
Methods: Liver ischemia was induced in male Wistar rats by occluding the portal vein with a microvascular clip for 30 minutes. Rats received two intramuscular injections of AZA (4 mg/kg), CsA (5 mg/kg), FK506 (0.5 mg/kg), or RPM (0.5 mg/kg) 3 and 24 hours before ischemia/reperfusion of the liver.
Results: Serum CINC concentrations in untreated animals increased, peaked 6 hours after reperfusion, and thereafter decreased gradually. Pretreatment with AZA, CsA, FK506, and RPM, however, inhibited the increase in serum CINC concentrations after reperfusion. CINC mRNA in liver tissue increased and peaked 3 hours after reperfusion, but was significantly lower in animals treated with AZA, CsA, FK506, and RPM. In vitro CINC production by Kupffer cells harvested from animals treated with AZA, CsA, FK506, or RPM 3 hours after reperfusion was also significantly lower than that observed in untreated animals. Both myeloperoxidase activity and the number of neutrophils accumulating in the liver 24 hours after reperfusion in animals treated with AZA, CsA, FK506, and RPM were significantly lower than in untreated animals. This correlated with lower serum aspartate transaminase, alanine transaminase, and lactate dehydrogenase levels in animals treated with AZA, CsA, FK506, and RPM 24 hours after reperfusion.
Conclusion: The immunosuppressants AZA, CsA, FK506, and RPM reduce neutrophil accumulation and attenuate ischemia/reperfusion injury of the liver.
The Journal of Trauma and Acute Care Surgery. 02/1998; 44(3):475-484.
